The proposed research involves using advanced computational methods to determine and understand the key factors responsible for ligand-receptor interactions. Such an understanding can lead to the design of therapeutic agents that exhibit greater specificity, tighter binding, and enhanced recognition of biological targets. The project focuses on the determination of the structural and energetic contributions that to sequence specific recognition of DNA by minor groove binding ligands. The ligands of interest, designed imidazole-pyrrole polyamide type, have shown promise in controlling gene expression. A high resolution solution structure of a6- ring, cyclic polyamide bound to a DNA oligomer will be determined using NMR-derived data and solvated molecular dynamics simulations. Free energy methods will be used to compute the absolute and relative binding affinities of a series of polyamide ligands in order to understand the mechanism by which a ligand discriminates between potential DNA sites. The proton chemical shifts of various protons in these will also be calculated to aid in assignment of the spectra.